CN102438606B - Coenzyme Q10 nanoparticles, preparation method thereof and composition containing said nanoparticles - Google Patents

Coenzyme Q10 nanoparticles, preparation method thereof and composition containing said nanoparticles Download PDF

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CN102438606B
CN102438606B CN201080020168.9A CN201080020168A CN102438606B CN 102438606 B CN102438606 B CN 102438606B CN 201080020168 A CN201080020168 A CN 201080020168A CN 102438606 B CN102438606 B CN 102438606B
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coenzyme
cozymase
protein
nano
solubilising
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CN102438606A (en
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郑凤铉
韩正贤
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Korea Research Institute of Bioscience and Biotechnology KRIBB
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    • B82—NANOTECHNOLOGY
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    • B82B3/00—Manufacture or treatment of nanostructures by manipulation of individual atoms or molecules, or limited collections of atoms or molecules as discrete units
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C30—CRYSTAL GROWTH
    • C30B—SINGLE-CRYSTAL GROWTH; UNIDIRECTIONAL SOLIDIFICATION OF EUTECTIC MATERIAL OR UNIDIRECTIONAL DEMIXING OF EUTECTOID MATERIAL; REFINING BY ZONE-MELTING OF MATERIAL; PRODUCTION OF A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; SINGLE CRYSTALS OR HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; AFTER-TREATMENT OF SINGLE CRYSTALS OR A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; APPARATUS THEREFOR
    • C30B33/00—After-treatment of single crystals or homogeneous polycrystalline material with defined structure
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01L—SEMICONDUCTOR DEVICES NOT COVERED BY CLASS H10
    • H01L21/00—Processes or apparatus adapted for the manufacture or treatment of semiconductor or solid state devices or of parts thereof
    • H01L21/02—Manufacture or treatment of semiconductor devices or of parts thereof
    • H01L21/04—Manufacture or treatment of semiconductor devices or of parts thereof the devices having at least one potential-jump barrier or surface barrier, e.g. PN junction, depletion layer or carrier concentration layer
    • H01L21/18—Manufacture or treatment of semiconductor devices or of parts thereof the devices having at least one potential-jump barrier or surface barrier, e.g. PN junction, depletion layer or carrier concentration layer the devices having semiconductor bodies comprising elements of Group IV of the Periodic System or AIIIBV compounds with or without impurities, e.g. doping materials
    • H01L21/30—Treatment of semiconductor bodies using processes or apparatus not provided for in groups H01L21/20 - H01L21/26
    • H01L21/302—Treatment of semiconductor bodies using processes or apparatus not provided for in groups H01L21/20 - H01L21/26 to change their surface-physical characteristics or shape, e.g. etching, polishing, cutting
    • H01L21/306—Chemical or electrical treatment, e.g. electrolytic etching
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes

Abstract

The present invention relates to coenzyme Q10 nanoparticles, a preparation method thereof and a composition containing the nanoparticles. According to the present invention, coenzyme Q10 can be dissolved in a water-miscible organic solvent alone, easily made in a nanoparticulated and soluble form through simple stirring which is a low-energy condition, and dispersion-stabilized by amino acids or proteins. As the coenzyme Q10 is dissolved in nanoscale size, absorption rate increases. As amino acids and proteins can be delivered together with the nanoparticles, the effective use of coenzyme Q10 in food, cosmetics and medicine is also possible.

Description

Cozymase Q 10 nano granule, its preparation method and the compositions that comprises described nano-particle
Technical field
The present invention relates to a kind of cozymase Q 10 nano granule, its preparation method and the compositions that contains described nano-particle.
Background technology
Coenzyme Q10 is called ubidecarenone, is a kind of ubiquinone (C being present in higher mammal 59h 90o 4, molecular weight: 863.34), it has 10 isoprene units on 2,3-dimethoxy-5-methyl-6-polyisopreneyl-Isosorbide-5-Nitrae-benzoquinone side chain.As everyone knows, coenzyme Q10 is not only used as coenzyme, but also improves oxygen usefulness as vitamin-like material.In addition, coenzyme Q10 is absolutely necessary for producing in mitochondrion adenosine triphosphate according to reports, and reports it and improve immunity and heart disease, hypertension, valvular heart disease, alveolitis etc. are had to effect.Coenzyme Q10 contributes to prevent congestive heart failure, cerebrovascular occlusion and anticancer durg side effect (heart source sexual disorder that prevention is caused by amycin), contributes to fatigue recovery, energy regeneration and the Oxidation of resistant activity oxygen in live organism simultaneously.In addition, estimate that it works as external preparation for skin, demonstrates anti-aging effects thus.
But coenzyme Q10 dissolubility in water is very poor, and stability reduces with the variation of light, heat or pH.Therefore, carrying out various research to guarantee the stability of coenzyme Q10 and to increase its absorbance.
Make the routine techniques of water insoluble active ingredient solubilising as follows.
Japanese Patent Publication No.60-199814 discloses a kind of lipomul, and it uses nonionic surfactant (for example Polyethylene Glycol or castor oil hydrogenated polyoxyethylene-(20)-ether) and uses Manton Gaulin type high pressure homogenizer (500-550kg/cm 2) process.
European patent No.494651B1 and U.S. Patent No. 5298246 disclose a kind of compositions, it is by being dissolved in ubiquinone in butterfat and obtaining, utilize fat globule membrane emulsifying gained ubiquinone solution and be the diameter with 1 to 5 μ m by gradation, thereby improve trap.
In addition, Korean Patent No.10-0835250 discloses a kind of method of preparing self emulsifying carrier.In this patent, the method comprises insoluble water active component is dissolved in non-polar oil equably, lecithin is joined in polyhydric alcohol, at elevated temperatures gained solution is stirred together with surfactant, by adding non-polar oil (being wherein dissolved with described water unmixability active component) this solution of pre-emulsification (wherein dispersed have lecithin), and make described pre-emulsion pass through microfluidizer.
Korean Patent No.10-0463167 discloses and has comprised the method for coenzyme Q10 as the percutaneous nano-particle of active component a kind of preparation, the method comprises: insoluble polymer (for example polymethyl methacrylate) and the coenzyme Q10 that is insoluble to live organism are dissolved in organic solvent, described organic solvent is not easy to miscible with water and (does not for example have extra high boiling point, dichloromethane), by carrying out first emulsifying and utilize high-pressure emulsification device (pressure: 500 to 1500bar in the aqueous solution that comprises surfactant, flow velocity: 20 to 150ml/ minute) carry out emulsifying for the second time and produce nano-emulsion, remove dichloromethane and process this Emulsion by solvent extraction.
In addition, the open No.2008/0160095 of United States Patent (USP) discloses a kind of method that particle diameter is 160 to 220nm taxol nanoparticle of preparing, the method comprises water-fast paclitaxel is dissolved in chloroform, gained solution is joined in human serum albumin's aqueous solution and stirred first, utilize high pressure homogenizer under 9000 to 40000psi high pressure, to prepare the paclitaxel nano Emulsion of albumin-binding, and organic solvent is removed in decompression at 40 ℃.According to the method, in the time of independent use water miscible solvent, form the crystalline particle having from nanometer to micron different-grain diameter.Due to this reason, for only forming the granule of nano-scale, water unmixability solvent should be used together with water miscible solvent, and should use the equipment that needs highly energy-consuming, for example high pressure homogenizer.
As mentioned above, these make the conventional method of the insoluble active component solubilising of water use different additive (comprising emulsifying agent), energy that need to be a large amount of and the some steps of process, this is because these methods are used heating, tentatively stirring and twice dispersing under high pressure.
Summary of the invention
The present invention relates to provide a kind of cozymase Q 10 nano granule, wherein water-insoluble coenzyme Q10 is by solubilize, and therefore absorbance increases.
The invention still further relates to provides a kind of and utilizes straightforward procedure and the low-yield method of preparing cozymase Q 10 nano granule to enhance productivity, and relates to the compositions that contains described nano-particle.
On the one hand, the invention provides a kind of be selected from amino acid and protein in the cozymase Q 10 nano granule that combines of at least one or two components.Other aspects of the present invention provide a kind of method of preparing cozymase Q 10 nano granule, it,, by coenzyme Q10 being only dissolved in water miscible solvent, adding aminoacid or protein and remove described water miscible solvent and realize in gained solution, the invention still further relates to the compositions that contains described cozymase Q 10 nano granule.
According to the present invention, coenzyme Q10 can only dissolve in the miscible property of water organic solvent, is easy to make the granule of nano-scale and (for example passes through simple agitation) under low energy condition dissolving, and by aminoacid or protein stably dispersing.Because coenzyme Q10 forms with the granule of nano-scale and by solubilising, therefore absorbance can improve and amino acid and protein can be sent with nano-particle simultaneously.Therefore, this cozymase Q 10 nano granule can be effective in food, cosmetics and medicine.
Accompanying drawing explanation
By to the detailed description of illustrative embodiments of the invention by reference to the accompanying drawings, it is more apparent that above and other object of the present invention, Characteristics and advantages will become to those skilled in the art.Wherein:
Fig. 1 is the grading curve that utilizes the cozymase Q 10 nano granule of cysteine solubilising;
Fig. 2 is the grading curve that utilizes the cozymase Q 10 nano granule of serine solubilising;
Fig. 3 is the grading curve that utilizes the cozymase Q 10 nano granule of the gelatin solubilising extracting from fish skin;
Fig. 4 is the grading curve that utilizes the cozymase Q 10 nano granule of the gelatin solubilising extracting from Corii Sus domestica;
Fig. 5 is the grading curve that utilizes the cozymase Q 10 nano granule of the gelatin solubilising extracting from Corii Bovis seu Bubali;
Fig. 6 is the grading curve that utilizes the cozymase Q 10 nano granule of white of an egg albumin solubilising;
Fig. 7 is the grading curve that utilizes the cozymase Q 10 nano granule of bovine serum albumin solubilising;
Fig. 8 is the grading curve that utilizes the cozymase Q 10 nano granule of human serum albumin's solubilising;
Fig. 9 has shown 1. coenzyme Q10 powder, 2. in the time that coenzyme Q10 is water-soluble, has been divided into the aqueous solution of supernatant layer and 3. utilizes the picture of the translucent yellow aqueous solution that the coenzyme Q10 of bovine serum albumin solubilising forms;
Figure 10 is transmission electron microscope (TEM) picture that utilizes the cozymase Q 10 nano granule of bovine serum albumin solubilising; With
Figure 11 is the figure that shows the long dispersion stability of the cozymase Q 10 nano granule that utilizes human serum albumin's solubilising.The detailed description of exemplary
Hereinafter will describe exemplary of the present invention in detail.
The present invention relates to a kind of be selected from amino acid and protein in the cozymase Q 10 nano granule that combines of at least one or two components.
Cozymase Q 10 nano granule in conjunction with aminoacid or protein can obtain by following steps: coenzyme Q10 is dissolved in the miscible property of the water organic solvent with water affinity, add to comprise to gained solution be selected from the solution of at least one or two components in amino acid and protein and stir this mixed solution, and remove organic solvent.The combination of described aminoacid or protein and coenzyme Q10 can be physical property combination, for example hydrophobic interaction, hydrogen bond, electrostatic interaction or Van der Waals force.Because the described cozymase Q 10 nano granule that is attached to aminoacid or protein is by aminoacid or protein protection, therefore it can be stable with water-soluble, and in aqueous solution, does not assemble or because it floats on the water than water viscosity is low.Therefore, the invention provides a kind of cozymase Q 10 nano granule, its water soluble, thereby be easily absorbed by the body and there is the stability of raising.Prepare be selected from amino acid and protein at least one cozymase Q 10 nano granule combining, described amino acid and protein can use separately or be mixed with each other.
In an exemplary of the present invention, described aminoacid can be at least one being selected from cysteine and serine.
In another exemplary of the present invention, described aminoacid also can comprise water-soluble amino acid.For example, described water-soluble amino acid can be at least one being selected from methionine, arginine, glycine, glutamine, threonine, proline, isoleucine, alanine, lysine and glutamic acid.
In another exemplary of the present invention, described protein can be at least one being selected from gelatin, albumin, Fibrinogen, lysozyme, silk-fibroin(s), sericin, trypsinogen and pepsin.It is reported, gelatin or serum albumin have adsorption (such as hydrophobic bonding or electrostatical binding) and the colloidal solid realized by this adsorption decentralized stabilization function (the Lakshmi-narasimhan Krishnamurthy etc. in solution, Journal of Colloid and Interface Science, 280,264-275,2004).
In another exemplary of the present invention, described protein can also comprise water soluble protein.
In an exemplary of the present invention, with respect to the coenzyme Q10 of 1 weight portion, amino acid whose content can be 0.5 to 100 weight portion.In the time that amino acid whose content is less than 0.5 weight portion, aminoacid may be not enough to wrap up coenzyme Q10 and therefore coenzyme Q10 may not be stabilized; In the time that amino acid whose content is greater than 100 weight portion, the cozymase Q 10 nano granule of institute's solubilising may cannot be prepared because viscosity is high.
In another exemplary of the present invention, with respect to the coenzyme Q10 of 1 weight portion, the content of protein can be 0.5 to 100 weight portion.In the time that the content of protein is less than 0.5 weight portion, protein may be not enough to wrap up coenzyme Q10 and therefore coenzyme Q10 may not be stabilized; In the time that the content of protein is greater than 100 weight portion, the cozymase Q 10 nano granule of institute's solubilising may cannot be prepared because viscosity is high.
The present invention also provides a kind of method of the cozymase Q 10 nano granule of preparing solubilising.This detailed method comprises: 1) prepare by coenzyme Q10 being dissolved in the miscible property of water organic solvent the mixed solution that is dissolved with coenzyme Q10; 2) by by 1) in the mixed solution of preparation join comprise in the aqueous solution that is selected from least one or two components in amino acid and protein, prepare be selected from amino acid and protein in the cozymase Q 10 nano granule that combines of at least one or two components, and stir this gained mixture; And 3) remove the miscible property of described water organic solvent.
Step 1) be characterised in that and coenzyme Q10 be only dissolved in the miscible property of water organic solvent and do not use emulsifying agent, surfactant or various additive.The miscible property of described water organic solvent can be but be not limited to be selected from dimethyl formamide (DMF), dimethyl acetylamide (DMAc), N-Methyl pyrrolidone, ketopyrrolidine, 1,3-dimethyl-3,4, one in 5,6-tetrahydrochysene-2 (1H)-pyrimidone (DMPU), hexamethyl phosphoramide (HMPA), acetone and acetonitrile.
In step 2) in, when by step 1) in the mixed solution of preparation join when comprising in the aqueous solution that is selected from least one or two components in amino acid and protein and stirring this gained mixture, the miscible property of water organic solvent is diffused into rapidly in water and coenzyme Q10 is combined with amino acid and protein, thereby is formed on the cozymase Q 10 nano granule of the solubilising in this aqueous solution.According to the present invention, can make coenzyme Q10 solubilising and prepare on nanometer level by simple agitation under low energy level, and needn't use high energy homogenizer of the prior art or homo-mixer.In one exemplary embodiment of the present invention, described simple agitation can 100 speed that arrive 1000rpm be implemented.
Prepare the cozymase Q 10 nano granule of solubilising of the present invention, described amino acid and protein can use separately or be mixed with each other.
In step 3) in, the method for removing the miscible property of described water organic solvent can be not limited to ad hoc approach, and can use method well known in the prior art.For example, when using when volatile solvent, can be with carrying out the method for evaporating solvent by stirring, come method or the freeze-drying of evaporating solvent by decompression.In some cases, organic solvent can be removed by optionally only separating relatively low-molecular-weight organic solvent with molecular weight mwco membrane filter.
For example, when by organic miscible described water property molten while removing, also can not carry out purification with described mwco membrane filter in conjunction with the macromolecular weight protein being retained in this aqueous solution of this coenzyme from the cozymase Q 10 nano granule of conjugated protein.But, in the time removing the miscible property of this water organic solvent with this mwco membrane filter from conjunction with amino acid whose cozymase Q 10 nano granule, be retained in not little and therefore by this mwco membrane filter in conjunction with the amino acid whose molecular weight of coenzyme Q10 in this aqueous solution.Therefore, remaining aminoacid is not reusable, therefore preferably aminoacid is carried out to lyophilization.
The present invention also provides a kind of compositions of the cozymase Q 10 nano granule that contains solubilising.
In an exemplary of the present invention, the compositions of the cozymase Q 10 nano granule that contains described solubilising can be food composition.
The purposes of said composition is not particularly limited, and therefore can be used for various food.The example of the food that comprises the compositions that contains this cozymase Q 10 nano granule can be but be not limited to beverage as soft drink, sports drink, soda pop, fruit drink, lactic acid beverage, alcoholic beverage, vitamin or mineral beverage and health beverage; Noodles are as Japanese noodle and spaghetti; Bread and snacks are as chocolate, bread, cookies, confection and fruit jelly; Frozen confectionery is as ice cream and frozen food; The milk product of processing and meat products are as Yoghourt and Petaso; Flavoring agent is as broad bean paste, soy sauce, liquid soup, curry and stuffing material; Processed food is as bean curd and noodles; And the oil and fat product of processing is as margarine, fat liquoring and shortening.In addition, comprise coenzyme Q10 and can prepare according to this area well-known method of common technique personnel for the food of the conventional additives of food.
In another exemplary of the present invention, the compositions of the cozymase Q 10 nano granule that contains described solubilising can be cosmetic composition.
Coenzyme Q10 has antioxidation, antiinflammatory, fatigue recovery, skin moisture-keeping and anti-aging effects, and the compositions that contains cozymase Q 10 nano granule described in therefore can be used for cosmetics.Can include but not limited to softening agent, Emulsion, massage cream, moisturizer, Liniment, gel, quintessence oil, lip pomade, sun screen, foundation cream, washing liquid, ointment, gel, emulsifiable paste, abluent, cleaning agent, soap, shampoo, purificant, treatment and cosmetic liquid according to the preparation of cosmetic composition of the present invention.These cosmetics can comprise conventional component as water soluble vitamins, fat soluble vitamin, polypeptide, polysaccharide or sphingolipid, and can easily prepare according to the well-known technology of those of ordinary skills.In addition, said components can suitably be mixed with the additive that routine is used, described conventional additive for example antioxidant, ultra-violet protecting agent, exfoliator, surfactant, aromatic, pigment, antiseptic, pH adjusting agent or the chelating agen using.
The compositions of the cozymase Q 10 nano granule that in yet another embodiment of the present invention, contains described solubilising can be pharmaceutical composition.
The known function with promotion antioxidation, antiinflammatory and immunostimulation of coenzyme Q10.Therefore, comprise of the present invention be selected from amino acid and protein in the pharmaceutical composition of the cozymase Q 10 nano granule that combines of at least one component be not limited to be used for the treatment of the pharmaceutical composition of specified disease, and can be used as estimating the additional activity composition of the medicine with above-mentioned effect.For example, described compositions can be used for but is not limited to the resultful medicine of heart disease, hypertension, valvular heart disease, alveolitis, congestive heart failure, cerebrovascular occlusion and anticancer durg side effect (heart source sexual disorder that prevention is caused by amycin).
Except active component, this pharmaceutical composition also can with on suitable and physiology pharmaceutically can with adjuvant prepare, the example of described adjuvant can comprise that solubilizing agent is as excipient, disintegrating agent, sweeting agent, binding agent, coating materials, foaming agent, lubricant, brightener and flavoring agent.
Pharmaceutical composition of the present invention is preferably formulated as and except active component, also comprises at least one pharmaceutically suitable carrier and be beneficial to use.
The example that is used for pharmaceutically suitable carrier of the compositions that is formulated in liquid solution can comprise saline, aquesterilisa, ringer's solution, buffer saline, albumin Injectable solution, glucose solution, maltodextrin solution, glycerol, ethanol and be suitable for sterilizing and its mixture a kind of or various ingredients of living organism.Also can add if desired other conventional additives, as antioxidant, buffer agent or antibacterial.In addition, described pharmaceutical composition can be formulated as injectable dosage forms (as aqueous solution, suspension or muddy fluid), and by adding diluent, dispersant, surfactant, binding agent and lubricant to prepare pill, capsule, granule or tablet.In addition, described pharmaceutical composition preferably also uses at Remington ' s Pharmaceutical Science according to disease or component, Mack Publishing Company, and in Easton PA prepared by the applicable method of disclosed association area.
The dosage form type of pharmaceutical composition of the present invention can be granule, powder, coated tablet, pill, capsule, suppository, syrup, juice, suspension, Emulsion, drop or injectable fluid and the sustained release forms of reactive compound.
Pharmaceutical composition of the present invention can be by conventional route via in intravenous, intra-arterial, intraperitoneal, intramuscular, intra-arterial, intraperitoneal, breastbone, use in percutaneous, per nasal, suction, part, rectum, oral, ophthalmic or blood.
The effective dose of the active component of pharmaceutical composition of the present invention means prevention or treatment disease or the resultful aequum of induced growth.Therefore, this effective dose can be according to various factors and difference, described factor comprise the kind of the active component that comprises in kinds of Diseases, disease severity, compositions and other components and content, type of dosage form, patient age, body weight, general health situation, sex and diet, time of application, use by way of with rate of release, the treatment persistent period of compositions and the medicine simultaneously using.For example, for adult, the effective dose of coenzyme Q10 can be 1 to 100 milligram/kg every day, and coenzyme Q10 can once-a-day administration, or uses with the dosage separating.
Pharmaceutical composition of the present invention can be applied to (but being not limited to) people, orangutan, chimpanzee, mice, rat, Canis familiaris L., cattle, chicken, pig, goat or sheep.
Embodiment
Describe the present invention in detail below with reference to embodiment, to help understanding the present invention.But the following example only provides for describing the present invention, rather than limits the scope of the invention.Provide embodiments of the invention, to explain the present invention completely to those of ordinary skills.
< embodiment 1> utilizes the preparation of the cozymase Q 10 nano granule of cysteine solubilising
5 milligrams of coenzyme Q10s are dissolved in 1 milliliter of acetone.Under 500rpm stirs, this mixed solution is added to rapidly in 30 milliliter of 1% cysteine aqueous solution, disperse so that then coenzyme Q10 solubilising stirs 6 hours to remove desolventizing under 500rpm.Be dispersed with the yellow that the aqueous solution of cozymase Q 10 nano granule is translucent.The cozymase Q 10 nano granule aqueous solution of described solubilising is kept to 4 ℃.
Fig. 1 is the grading curve with the nano-particle of the embodiment 1 of laser light scattering instrument (ELS-Z, Otsuka, Japan) mensuration.It has confirmed that the nano-particle of solubilising has 135 to 280nm average particle size distribution.
< embodiment 2> utilizes the preparation of the cozymase Q 10 nano granule of serine solubilising
5 milligrams of coenzyme Q10s are dissolved in 1 milliliter of N-Methyl pyrrolidone.Under stirring, mixed solution is added to rapidly in 30 milliliter of 1% serine aqueous solution 500rpm, disperse so that coenzyme Q10 solubilising uses freezer dryer (EYELAFDU-2100, EYELA afterwards, Japan) lyophilizing 24 hours under 20 ℃ of decompressions, obtain thus pale yellow powder.Then, described powder is dispersed in aquesterilisa again, observes and be dispersed with the yellow that the aqueous solution of cozymase Q 10 nano granule is translucent.The cozymase Q 10 nano granule aqueous solution of described solubilising is kept to 4 ℃.
Fig. 2 is the grading curve with the nano-particle of the embodiment 2 of laser light scattering instrument (ELS-Z, Otsuka, Japan) mensuration.It has confirmed that the nano-particle of solubilising has 70 to 315nm average particle size distribution.
< embodiment 3> utilizes the preparation of the cozymase Q 10 nano granule of the gelatin solubilising extracting from fish skin
10 milligrams of coenzyme Q10s are dissolved in 1 milliliter of N-Methyl pyrrolidone.Under 500rpm stirs, this mixed solution is added to rapidly the aqueous solution of gelatin extracting from fish skin of 30 milliliter 1%, disperse so that coenzyme Q10 solubilising.Afterwards, remove low-molecular-weight organic solvent with molecular weight mwco membrane filter, be dispersed with the yellow that the aqueous solution of this cozymase Q 10 nano granule is translucent.The cozymase Q 10 nano granule aqueous solution of described solubilising is kept to 4 ℃.
Fig. 3 is the grading curve with the nano-particle of the embodiment 3 of laser light scattering instrument (ELS-Z, Otsuka, Japan) mensuration.It has confirmed that the nano-particle of this solubilising has the average particle size distribution of 110 to 550 nanometers.
< embodiment 4> utilizes the preparation of the cozymase Q 10 nano granule of the gelatin solubilising extracting from Corii Sus domestica
Except using the gelatin extracting from Corii Sus domestica, undertaken by the described method of embodiment 3.
Fig. 4 is the grading curve with the nano-particle of the embodiment 4 of laser light scattering instrument (ELS-Z, Otsuka, Japan) mensuration.It has confirmed that the nano-particle of this solubilising has the average particle size distribution of 250 to 850 nanometers.
< embodiment 5> utilizes the preparation of the cozymase Q 10 nano granule of the gelatin solubilising extracting from Corii Bovis seu Bubali
Except using the gelatin extracting from Corii Bovis seu Bubali, undertaken by the described method of embodiment 3.
Fig. 5 is the grading curve with the nano-particle of the embodiment 5 of laser light scattering instrument (ELS-Z, Otsuka, Japan) mensuration.It has confirmed that the nano-particle of this solubilising has the average particle size distribution of 100 to 700 nanometers.
< embodiment 6> utilizes the preparation of the cozymase Q 10 nano granule of white of an egg albumin solubilising
Except using white of an egg albumin, undertaken by the described method of embodiment 3.
Fig. 6 is the grading curve with the nano-particle of the embodiment 6 of laser light scattering instrument (ELS-Z, Otsuka, Japan) mensuration.It has confirmed that the nano-particle of this solubilising has the average particle size distribution of 40 to 300 nanometers.
< embodiment 7> utilizes the preparation of the cozymase Q 10 nano granule of bovine serum albumin solubilising
Except using bovine serum albumin ultrawhite, undertaken by the described method of embodiment 3.
Fig. 7 is the grading curve with the nano-particle of the embodiment 7 of laser light scattering instrument (ELS-Z, Otsuka, Japan) mensuration.It has confirmed that the nano-particle of this solubilising has the average particle size distribution of 70 to 500 nanometers.
< embodiment 8> utilizes the preparation of the cozymase Q 10 nano granule of human serum albumin's solubilising
Except end user's serum albumin, undertaken by the described method of embodiment 3.
Fig. 8 is the grading curve with the nano-particle of the embodiment 8 of laser light scattering instrument (ELS-Z, Otsuka, Japan) mensuration.It has confirmed that the nano-particle of this solubilising has the average particle size distribution of 70 to 400 nanometers.
In embodiment 1 to 8, the laser light scattering instrument for particle diameter (ELS-Z, Otsuka, Japan) of the nano-particle of preparation is measured three cycles.In each cycle, carry out diameter measurement 100 times.Therefore the average diameter of particles of, measuring in the method is as shown in table 1.
Table 1
Sample title Average diameter of particles (nm) Standard deviation (±)
Cysteine (aminoacid) 250.5 49.4
Serine (aminoacid) 190.4 40.1
Gelatin (extracting from fish skin) 223.4 5.5
Gelatin (extracting from Corii Sus domestica) 423.9 1.5
Gelatin (extracting from Corii Bovis seu Bubali) 264.6 10.8
Albumin (white of an egg) 95.9 1.9
Albumin (Ox blood serum) 244.2 38.6
Albumin (human serum) 151.3 2.7
The confirmation of < experimental example 1> cozymase Q 10 nano granule solubilising
1. Fig. 9 has shown coenzyme Q10 powder, 2. in the time that coenzyme Q10 is scattered in water, has been divided into the aqueous solution of supernatant layer and the 3. aqueous solution of the cozymase Q 10 nano granule of the embodiment of the present invention 7.
As seen in Figure 9, this insoluble coenzyme Q10 is due to the water insoluble layer separating with water that formed, itself and albumin bound, and therefore become water soluble.Result forms translucent yellow aqueous solution.
< experimental example 2> uses the observation of transmission electron microscope to cozymase Q 10 nano granule
For observing the shape of the nano-particle of preparation in embodiment 7, by the nano-particle of described protein solubilising at 4 ℃ of centrifuge washings three times under 17000rpm, then for the preparation of the sample that uses transmission electron microscope (FE-TEM, JEOL, Japan) to observe.
Figure 10 is the TEM picture that utilizes the cozymase Q 10 nano granule of bovine serum albumin solubilising.The visible cozymase Q 10 nano granule being wrapped up by bovine serum albumin is black.
The confirmation of < experimental example 3> cozymase Q 10 nano granule stability
For the long-time stability of check cozymase Q 10 nano granule aqueous solution, points three groups utilize the method described in embodiment 8 to prepare translucent yellow aqueous solution, and at room temperature keep away ultraviolet and keep 5 months.At this, monthly measure mean diameter with check dispersion stabilization.This experiment is carried out under sterilising conditions, and does not use antiseptic or additive.
Figure 11 shows the long dispersion stability of the cozymase Q 10 nano granule that utilizes human serum albumin's solubilising.It confirms even preparing this cozymase Q 10 nano granule after 5 months, and the average particulate diameter of this nano-particle does not still have significant change.
The preparation of < preparation example 1> clear gel type solubilize dosage form
In preparation example 1, prepare clear gel type solubilize dosage form by the composition shown in table 2.The viscosity of said preparation is approximately 4000cps.Meanwhile, this viscosity is used Brookfield (LVDVII+) to measure with 12rpm at 30 ℃.
Table 2
Component (content: % by weight) Preparation example 1
Glycerol 5
Propylene glycol 4
The cozymase Q 10 nano granule of embodiment 7 5
Ethanol 10
Sodium polyacrylate 0.5
Antiseptic In right amount
Distilled water Add to 100
The preparation of the opaque gel-type solubilize of < preparation example 2> dosage form
In preparation example 2, prepare opaque gel-type solubilize dosage form by the composition shown in table 3.By each dissolving completely at 70 ℃ in oil phase prepared product and water prepared product, with 7000rpm emulsifying 5 minutes, prepare thus opaque gel-type lotion.The viscosity of this lotion is about 2500cps.Meanwhile, this viscosity is used brookfield (LVDVII+) to measure with 12rpm at 30 ℃.
Table 3
Figure GSB00000745739500121
The preparation of < preparation example 3> emulsifiable paste dosage form
In preparation example 3, prepare emulsifiable paste dosage form by the composition shown in table 4.Preparation process is identical with description in preparation example 2.
Table 4
Figure GSB00000745739500122

Claims (4)

1. a method of preparing the cozymase Q 10 nano granule of solubilising, comprising:
1) by coenzyme Q10 being dissolved in to the mixed solution of preparing the coenzyme Q10 of dissolving in the miscible property of the water organic solvent with water affinity;
2) by by step 1) in the mixed solution of preparation add to comprise in the aqueous solution that is selected from least one or two components in amino acid and protein and stir gained mixture prepare be selected from amino acid and protein in the cozymase Q 10 nano granule that combines of at least one or two components; And
3) remove the miscible property of described water organic solvent,
Wherein said aminoacid is at least one being selected from cysteine and serine;
Wherein said protein is at least one being selected from gelatin and albumin;
Wherein, with respect to the coenzyme Q10 of 1 weight portion, described amino acid whose content is 0.5 to 100 weight portion;
Wherein, with respect to the coenzyme Q10 of 1 weight portion, the content of described protein is 0.5 to 100 weight portion.
2. according to the method for claim 1, the miscible property of wherein said water organic solvent is to be selected from dimethyl formamide (DMF), dimethyl acetylamide (DMAc), N-Methyl pyrrolidone, ketopyrrolidine, 1,3-dimethyl-3,4, at least one in 5,6-tetrahydrochysene-2 (1H) pyrimidones (DMPU), hexamethyl phosphoramide (HMPA), acetone and acetonitrile.
3. be 0.001 to 50% according to comprising the concentration that is selected from the aqueous solution of at least one or two components in amino acid and protein described in the process of claim 1 wherein.
4. described except the miscible property organic solvent that anhydrates is by stirring lower evaporating solvent, the lower evaporating solvent of decompression, lyophilization or carrying out with mwco membrane filter according to the process of claim 1 wherein.
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